6-5, 6-6, or 6-7 Heterobicycles as factor Xa inhibitors

ABSTRACT

The present application describes 6–5, 6—6, or 6–7 heterobicycles of Formula I or pharmaceutically acceptable salt forms thereof:                  
 
wherein ring P is a 6-membered heteroaromatic and ring M is a 5-, 6-, or 7-membered non-aromatic carbocycle or heterocycle. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.

FIELD OF THE INVENTION

This invention relates generally to 6–5, 6—6, or 6–7 heterobicycles, which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.

BACKGROUND OF THE INVENTION

WO94/20460 describes angiotensin II compounds of the following formula:

wherein X can be a number of substituents and Het can be a nitrogen-containing heterobicycle. However, WO94/20460 does not suggest Factor xa inhibition or exemplify compounds like those of the present invention.

WO96/12720 describes phosphodiesterase type IV and TNF production inhibitors of the following formula:

wherein X can be oxygen and R² and R³ can a number of substituents including heterocycle, heterocycloalkyl, and phenyl. However, the presently claimed compounds do not correspond to the compounds of WO96/12720. Furthermore, WO96/12720 does not suggest Factor Xa inhibition.

WO98/52948 describes inhibitors of ceramide-mediated signal transduction. One of the types of inhibitors described is of the following formula:

wherein Y₁ can be N—R₆, R₆ can be unsubstituted aryl-alkyl or unsubstituted heterocyclic-alkyl and R₁ can be a substituted aryl group. WO98/52948 does not mention factor Xa inhibition or show compounds like those of the present invention.

U.S. Pat. Nos. 3,365,459 and 3,340,269 illustrate anti-inflammatory inhibitors of the following formula:

wherein A is 2–3 carbon atoms, X can be O, and R¹ and R³ can be substituted or unsubstituted aromatic groups. Neither of these patents, however, exemplify compounds of the present invention.

WO99/50257 provides compounds of the general formula shown below as inhibitors of Factor Xa.

U.S. Pat. No. 5,252,584 shows hydroxyquinolones of the following formula.

R¹ can be a substituted pyrone. These compounds are not described as being useful for inhibiting factor Xa and are not considered to be part of the present invention.

WO99/32477 reports Factor Xa inhibitors of the following formula:

wherein the inhibitors contain at least three aryl or heterocyclic groups (i.e., C, B, and R³) separated by two linking groups (i.e., E and D). Compounds of this sort are not considered to be part of the present invention.

WO99/00121, WO99/00126, WO99/00127, and WO99/00128 describe Factor Xa inhibitors of the following formula:

wherein two of A³, A⁴, A⁵, and A⁶ may form a fused benz ring or A³ and A⁴ may form a fused benz ring while A⁵ and A⁶ together form NH. Compounds of this sort are not considered to be part of the present invention.

WO01/19798 describes factor Xa inhibitors of the following formula: A-Q-D-E-G-J-X wherein A, D, G. and X can be phenyl or heterocycle. However, none of the presently claimed compounds are exemplified or suggested in WO01/19798.

Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617–629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel nitrogen containing heterobicycles that are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder

It is another object of the present invention to provide a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.

It is another object of the present invention to provide novel compounds for use in therapy.

It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of a thromboembolic disorder.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that the presently claimed bicyclic compounds, or pharmaceutically acceptable salt or prodrug forms thereof, are effective factor Xa inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in an embodiment, the present invention provides a novel compound of formula I:

-   or a stereoisomer or pharmaceutically acceptable salt thereof,     wherein; -   ring M, including M₁ and M₂, is a 5, 6, or 7 membered carbocycle or     5, 6, or 7 membered heterocycle, “consisting of: carbon atoms and     0–3 heteroatoms selected from O, S(O)_(p), N, and NZ²; -   ring M is substituted with 0–2 R^(1a) and 0–2 carbonyl groups, and,     comprises: 0–2 additional double bonds; -   ring P, including P₁, P₂, P₃, and P₄ is selected from group: -   ring P is substituted with 0–2 R^(1a); -   one of P₄ and M₃ is -Z-A-B and the other -G₁-G; -   G is a group of formula IIa or IIb: -   ring D, including the two atoms of Ring E to which it is attached,     is a 5–6 membered non-aromatic ring consisting of carbon atoms, 0–1     double bonds, and 0–2 heteroatoms selected from the group consisting     of N, O, and S(O)_(p), and D is substituted with 0–2 R; -   alternatively, ring D, including the two atoms of Ring E to which it     is attached, is a 5–6 membered aromatic system consisting of carbon     atoms and 0–2 heteroatoms selected from the group consisting of N,     O, and S(O)_(p), and D is substituted with 0–2 R; -   E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and     pyridazinyl, and is substituted with 1–2 R; -   alternatively, the bridging portion of ring D is absent, and ring E     is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,     pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl,     thienyl, and thiazolyl, and ring E is substituted with 1–2 R; -   alternatively, the bridging portion of ring D is absent, ring E is     selected from phenyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,     pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,     triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1     R and with a 5–6 membered heterocycle consisting of: carbon atoms     and 1–4 heteroatoms selected from the group consisting of N, O, and     S(O)_(p) substituted with 0–1 carbonyls, 1–2 R and having 0–3 ring     double bonds; -   R is selected from H, C₁₋₄ alkyl, F, Cl, Br, I, OH, OCH₃, OCH₂CH₃,     OCH(CH₃)₂, OCH₂CH₂CH₃, CN, C (═NR⁸) NR⁷R⁹, NHC (═NR⁸) NR⁷R⁹, NR⁸CH     (═NR⁷), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, C (═NH)NH₂, CH₂NH₂,     CH₂NH(C₁₋₃ alkyl), CH₂N(C₁₋₃ alkyl)₂, CH₂CH₂NH₂, CH₂CH₂NH(C₁₋₃     alkyl), CH₂CH₂N(C₁₋₃ alkyl)₂, (CR⁸R⁹)_(t)C(O)H, (CR⁸R⁹)_(t)C(O)R²C,     (CR⁸R⁹)_(t)NR⁷R⁸, (CR⁸R⁹)_(t)C(O)NR⁷R⁸, (CR⁸R⁹)_(t)NR⁷C(O)R⁷,     (CR⁸R⁹)_(t)OR³, (CR⁸R⁹)_(t)S(O)_(p)NR⁷R⁸, (CR⁸R⁹)_(t)NR⁷S(O)_(p)R⁷,     (CR⁸R⁹)_(t)SR³, (CR⁸R⁹)_(t)S(O)R³, (CR⁸R⁹)_(t)S(O)₂R³, and OCF₃,     provided that S(O)_(p)R⁷ forms other than S(O)₂H or S(O)H; -   alternatively, when 2 R groups are attached to adjacent atoms, they     combine to form methylenedioxy or ethylenedioxy; -   A is selected from:     -   C₃₋₁₀ carbocycle substituted with 0–2 R⁴, and     -   5–10 membered heterocycle consisting of: carbon atoms and 1–4         heteroatoms selected from the group consisting of N, O, and         S(O)_(p) substituted with 0–2 R⁴; -   B is selected from: Y, X—Y, (CH₂)₀₋₂C(O)NR²R^(2a),     (CH₂)₀₋₂NR²R^(2a), C(═NR²)NR²R^(2a), and NR²C(═NR²)NR²R^(2a),     provided that Z and B are attached to different atoms on A; -   G₁ is absent or is selected from (CR³R^(3a))₁₋₅,     (CR³R^(3a))₀₋₂CR³═CR³ (CR³R^(3a))₀₋₂,     (CR³R^(3a))₀₋₂C≡C(CR³R^(3a))₀₋₂, (CR³R^(3a))_(u)C(O)(CR³R^(3a))_(w),     (CR³R^(3a))_(u)C(O)O(CR³R^(3a))_(w),     (CR³R^(3a))_(u)O(CR³R^(3a))_(w), (CR³R^(3a))_(u)NR³ (CR³R^(3a))_(w),     (CR³R^(3a))_(u)C(O)NR³(CR³R^(3a))_(w),     (CR³R^(3a))_(u)NR³C(O)(CR³R^(3a)) _(w),     (CR³R^(3a))_(u)OC(O)NR³(CR³R^(3a))_(w),     (CR³R^(3a))_(u)NR³C(O)0(CR³R^(3a))_(w), (CR³R^(3a))_(u)NR³C(O)NR³     (CR³R^(3a))_(w), (CR³R^(3a))_(u)NR³C(S)NR³(CR³R^(3a))_(w),     (CR³R^(3a))_(u)S(CR³R^(3a))_(w), (CR³R^(3a))_(u)S(O)(CR³R^(3a))_(w),     (CR³R^(3a))_(u)S(O)₂(CR³R^(3a))_(w),     (CR³R^(3a))_(u)S(O)NR³(CR³R^(3a))_(w),     (CR³R^(3a))_(u)NR³S(O)₂(CR³R^(3a))_(w), (CR³R^(3a))_(u)S(O)₂NR³     (CR³R^(3a)), and (CR³R^(3a))_(u)NR³S(O)₂NR³(CR³R^(3a))_(w), wherein     u+w total 0, 1, 2, 3, or 4, provided that G₁ does not form a N—N,     N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond with either group to which it     is attached; -   X is selected from —(CR²R^(2a))₁₋₄—, —CR²(CR²R^(2b))(CH₂)_(t)—,     —C(O)— —C(═NR^(1c)) —CR²(NR^(1c)R²), —CR²(OR²)—, —CR²(SR²)—,     —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S—, —S(O)—, —S(O)₂—, SCR²R^(2a),     —S(O)CR²R^(2a)—, —S(O)₂CR²R^(2a)—, —CR²R^(2a)S—, —CR²R^(2a)S(O)—,     —CR²R^(2a)S(O)₂—, —S(O)₂NR²—, —NR²S(O)₂—, —NR²S(O)₂CR²R^(2a),     CR²R^(2a)S(O)₂NR²—NR²S(O)₂NR²—, —C(O)NR²—, —NR²C(O)—,     —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, CR²R^(2a)C(O)NR²—,     —CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—, —NR²C(O)NR²—, —NR²—,     —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, CR²R^(2a)O—, and OCR²R^(2a); -   Y is selected from:     -   C₃₋₁₀ carbocycle substituted with 0–2 R^(4a), and,     -   5–10 membered heterocycle consisting of: carbon atoms and 1–4         heteroatoms selected from the group consisting of N, O, and         S(O)_(p) substituted with 0–2 R^(4a); -   Z is absent or is selected from —(CR²R^(2a))₁₋₄—,     (CR²R^(2a))_(q)O(CR²R^(2a))_(q1),     (CR²R^(2a))_(q)NR³(CR²R^(2a))_(q1),     (CR²R^(2a))_(q)C(O)(CR²R^(2a))_(q1),     (CR²R^(2a))_(q)C(O)O(CR²R^(2a))_(q1),     (CR²R^(2a))_(q)OC(O)(CR²R^(2a))_(q1),     (CR²R^(2a))_(q)C(O)NR³(CR²R^(2a))_(q1),     (CH₂)_(q)NR³C(O)(CR²R^(2a))_(q1),     (CR²R^(2a))_(q)OC(O)O(CR²R^(2a))_(q1),     (CH₂)_(q)OC(O)NR³(CR²R^(2a))_(q1),     (CR²R^(2a))_(q)NR³C(O)O(CR²R^(2a))_(q1),     (CH₂)_(q)NR³C(O)NR³(CR²R^(2a))_(q1),     (CR²R^(2a))_(q)S(CR²R^(2a))_(q1),     (CR²R^(2a))_(q)S(O)(CR²R^(2a))_(q1), (CH₂)_(q)S(O)C(CR²R^(2a))_(q1),     (CR²R^(2a))_(q)SO₂NR³(CR²R^(2a))_(q1), (CH₂)_(q)NR³SO₂     (CR²R^(2a))_(q1), and (CR²R^(2a))_(q)NR³SO₂NR³(CR²R^(2a))_(q1),     wherein q+q1 total 0, 1, or 2, provided that Z does not form a N—N,     N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond with either group to which it     is attached; -   Z² is selected from H, C₁₋₄ alkyl, phenyl, benzyl, C(O)R³, and     S(O)_(p)R³C; -   R^(1a) is selected from H, —(CH₂)_(r)—R^(1b), —CH═CH—R^(1b),     NCH₂R^(1c), OCH₂R^(1c), SCH₂R^(1c), NH(CH₂)₂(CH₂)_(t)R^(1b),     O(CH₂)₂(CH₂)_(t)R^(1b), S(CH₂)₂(CH₂)_(t)R^(1b),     S(O)_(p)(CH₂)_(r)R^(1d), O(CH₂)_(r)R^(1d), NR³(CH₂)_(r)R^(1d),     OC(O)NR³(CH₂)_(r)R^(1d), NR³C(O)NR³(CH₂)_(r)R^(1d),     NR³C(O)O(CH₂)_(r)R^(1d), and NR³C(O)(CH₂)_(r)R^(1d), provided that     R^(1a) forms other than an N-halo, N—N, N—S, N—O, or N—CN bond; -   alternatively, when two R^(1a)s are attached to adjacent carbon     atoms, together with the atoms to which they are attached they form     a 5–7 membered ring consisting of: carbon atoms and 0–2 heteroatoms     selected from the group consisting of N, O, and S(O)_(p), this ring     being substituted with 0–2 R^(4b) and comprising: 0–3 double bonds; -   R^(1b) is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO,     (CF₂)_(r)CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c), OC(O)R²,     (CF₂)_(r)CO₂R^(2a), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR²,     C(═NR^(2c))NR²R^(2a), NR²C(O)R^(2b), NR²C(O)NHR^(2b),     NR²C(O)₂R^(2a), OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a),     C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆ carbocycle     substituted with 0–2 R^(4a), and 5–10 membered heterocycle     consisting of carbon atoms and from 1–4 heteroatoms selected from     the group consisting of N, O, and S(O)_(p) substituted with 0–2     R^(4a), provided that R^(1b) forms other than an N-halo, N—N, N—S,     N—O, or N—CN bond; -   R^(1c) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),     S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a); -   R^(1d) is selected from C₃₋₆ carbocycle substituted with 0–2 R^(4a),     and 5–10 membered heterocycle consisting of carbon atoms and from     1–4 heteroatoms selected from the group consisting of N, O, and     S(O)_(p) substituted with 0–2 R^(4a), provided that R^(1d) forms     other than an N—N, N—S, or N—O bond; -   R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,     C₃₋₆ carbocycle substituted with 0–2 R^(4b), a C₃₋₆     carbocyclic-CH₂-residue substituted with 0–2 R^(4b), and 5–6     membered heterocycle consisting of: carbon atoms and 1–4 heteroatoms     selected from the group consisting of N, O, and S(O)_(p) substituted     with 0–2 R^(4b), -   R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl,     benzyl, C₃₋₆ carbocycle substituted with 0–2 R^(4b), and 5–6     membered heterocycle consisting of: carbon atoms and 1–4 heteroatoms     selected from the group consisting of N, O, and S(O)_(p) substituted     with 0–2 R^(4b); -   R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆     alkyl, benzyl, C₃₋₆ carbocycle substituted with 0–2 R^(4b), and 5–6     membered heterocycle consisting of: carbon atoms and 1–4 heteroatoms     selected from the group consisting of N, O, and S(O)_(p) substituted     with 0–2 R^(4b); -   R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy,     C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0–2     R^(4b), and 5–6 membered heterocyclic system containing from 1–4     heteroatoms selected from the group consisting of N, O, and S(O)_(p)     substituted with 0–2 R^(4b); -   alternatively, R² and R^(2a), together with the atom to which they     are attached, combine to form a 5 or 6 membered saturated, partially     saturated or unsaturated ring substituted with 0–2 R^(4b) and     consisting of: 0–1 additional heteroatoms selected from the group     consisting of N, O, and S(O) -   R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl; -   R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, benzyl,     and phenyl; -   R^(3b), at each occurrence, is selected from H, C₁₋₄ alkyl, and     phenyl; -   R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, benzyl, and     phenyl; -   R^(3d), at each occurrence, is selected from H, C₁₋₄ alkyl, C₁₋₄     alkyl-phenyl, and C(═O)R^(3c); -   R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl,     Br, L, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a),     (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a),     C(═NR²)NR²R^(2a), C(═NS(O)₂R⁵)NR²R^(2a), NHC(═NR²)NR²R^(2a),     C(O)NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄     alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, NCH₂R^(1c), OCH₂R^(1c),     SCH₂R^(1c), N(CH₂)₂(CH₂)_(t)R^(1b), O(CH₂)₂(CH₂)_(t)R^(1b), and     S(CH₂)₂(CH₂)_(t)R^(1b); -   alternatively, one R⁴ is a 5–6 membered aromatic heterocycle     consisting of: carbon atoms and 1–4 heteroatoms selected from the     group consisting of N, O, and S(O)_(p); -   R^(4a) at each occurrence, is selected from H, ═O, (CH₂)_(r)OR²,     (CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, Cl, Br, F, I, C₁₋₄ alkyl,     s-CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b),     C(O)NR²R^(2a), (CH₂)_(r)N═CHOR³, C(O)NH(CH₂)₂NR²R^(2a),     NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a),     SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄     alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃; -   alternatively, one R^(4a) is phenyl substituted with 0–1 R⁵ or a 5–6     membered aromatic heterocycle consisting of: carbon atoms and 1–4     heteroatoms selected from the group consisting of N, O, and S(O)_(p)     substituted with 0–1 R⁵; -   R^(4b), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR³, F,     Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a),     (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a),     NR³C(O)NR³R^(3a), C(═NR³)NR³R^(3a), NR³C(NR³)NR³R^(3a),     SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³ O₂—C₁₋₄ alkyl, NR³SO₂CF₃,     NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl,     and (CF₂)_(r)CF₃; -   R⁵, at each occurrence, is selected from H, C₁₋₆ alkyl, ═O,     (CH₂)_(r)OR³, F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂,     (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR^(3c),     NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a), CH(═NOR^(3d)),     C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a),     NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl,     S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, (CF₂)_(r)CF₃,     phenyl substituted with 0–2 R⁶, naphthyl substituted with 0–2 R⁶,     and benzyl substituted with 0–2 R⁶; -   R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo,     C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b),     NR²C(O)R^(2b), NR²C(O)NR²R^(2a), C (═NH)NH₂, NHC (═NH)NH₂,     SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl; -   R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆     alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl,     C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄     alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄     alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and     phenyl C₁₋₄ alkoxycarbonyl; -   R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl, and     (CH₂)_(n)-phenyl; -   alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered     saturated, ring which contains from 0–1 additional heteroatoms     selected from the group consisting of N, O, and S(O)_(p); -   R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl, and (CH₂)     n-phenyl; -   n, at each occurrence, is selected from 0, 1, 2, and 3; -   p, at each occurrence, is selected from 0, 1, and 2; -   r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6; -   t, at each occurrence, is selected from 0, 1, 2, and 3; -   alternatively, when     -   (a) B is other than an optionally substituted carbocycle; and,     -   (b) G₁ is (CR³R^(3a))_(u)NR³(CR³R^(3a))_(w) and u+w is 1, 2, 3,         or 4, (CR³R^(3a))_(u)C(O)NR³(CR³R^(3a))_(w),         (CR³R^(3a))_(u)NR³C(O)(CR³R^(3a))_(w),         (CR³R^(3a))_(u)S(O)NR³(CR³R^(3a))_(w),         (CR³R^(3a))_(u)S(O)₂NR³(CR³R^(3a))_(w), or         (CR³R^(3a))_(u)NR³S(O)₂ (CR³R^(3a));         -   then Z is other than (CH₂)NR³, NR³(CH₂), (CH₂)NR³(CH₂),             (CH₂)(CH₂)NR³, NR³(CH₂)(CH₂), (CH₂)_(q)C(O)NR³(CH₂)_(q1),             (CH₂)_(q)NR³C(O)(CH₂)_(q1), (CH₂)_(q)SO₂NR³(CH₂)_(q1), or             (CH₂)_(q)NR³SO₂(CH₂)_(q1); -   alternatively, when     -   (a) B is other than an optionally substituted carbocycle; and,     -   (b) Z is (CH₂)NR³, NR³(CH₂), (CH₂)NR³(CH₂), (CH₂)(CH₂)NR³,         NR³(CH₂)(CH₂), (CH₂)_(q)C(O)NR³(CH₂)_(q1),         (CH₂)_(q)NR³C(O)(CH₂)_(q1), (CH₂)_(q)SO₂NR³(CH₂)_(q1), or         (CH₂)_(q)NR³SO₂(CH₂)_(q1);         -   then G₁ is other than (CR³R^(3a))_(u)NR³(CR³R^(3a))_(w) and             u+w is 1, 2, 3, or 4, (CR³R^(3a))_(u)C(O)NR³(CR³R^(3a))_(w),             (CR³R^(3a))_(u)NR³C(O)(CR³R^(3a))_(w),             (CR³R^(3a))_(u)S(O)NR³(CR³R^(3a))_(w),             (CR³R^(3a))_(u)S(O)₂NR³(CR³R^(3a))_(w), or             (CR³R^(3a))_(u)NR³S(O)₂ (CR³R^(3a))_(w).             [2] In a preferred embodiment, the present invention             provides a novel compound, wherein: -   ring M is substituted with 0–2 R^(1a) and is selected from the     group: -   ring P, including P₁, P₂, P₃, and P₄ is selected from group: -   ring P is substituted with 0–2 R^(1a); -   one of P₄ and M₃ is -Z-A-B and the other -G₁-G; -   G is selected from the group: -   A is selected from one of the following carbocyclic and heterocyclic     systems which are substituted with 0–2 R⁴;     -   phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,         morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl,         isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,         oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl,         1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,         1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,         1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,         1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,         benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl,         benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and         isoindazolyl; -   B is selected from Y, X—Y, CH₂NR²R^(2a), and CH₂CH₂NR²R^(2a); -   G₁ is absent or is selected from (CR³R^(3a))₁₋₃,     (CR³R^(3a))_(u)C(O)(CR³R^(3a))_(w), (CR³R^(3a))_(u)O(CR³R^(3a))_(w),     (CR³R^(3a))_(u)NR³(CR³R^(3a))_(w),     (CR³R^(3a))_(u)C(O)NR³(CR³R^(3a))_(w),     (CR³R^(3a))_(u)NR³C(O)(CR³R^(3a))_(w),     (CR³R^(3a))_(u)S(CR³R^(3a))_(w), (CR³R^(3a))_(u)S(O)CR³R^(3a))_(w),     (CR³R^(3a))_(u)S(O)₂(CR³R^(3a))_(w),     (CR³R^(3a))_(u)S(O)NR³(CR³R^(3a))_(w), and     (CR³R^(3a))_(u)S(O)₂NR³(CR³R^(3a))_(w), wherein u+w total 0, 1, or     2, provided that G₁ does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, or     NCH₂S bond with either group to which it is attached; -   X is selected from —(CR²R^(2a))₁₋₄—, —C(O)—, —C(═NR^(1c))—,     —CR²(NR^(1c)R²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —C(O)NR²—,     —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—,     —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)NR²—, —NR²—,     —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—; -   Y is selected from one of the following carbocyclic and heterocyclic     systems that are substituted with 0–2 R^(4a);     -   cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl,         piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl,         thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl,         isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,         oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl,         1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,         1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,         1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,         1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,         benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl,         benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and         isoindazolyl; -   alternatively, Y is selected from the following bicyclic heteroaryl     ring systems: -   K is selected from O, S, NH, and N; -   Z is absent or is selected from CH₂O, OCH₂, NH, CH₂NH, NHCH₂,     CH₂C(O)₁ C(O)CH₂, C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and     NHSO₂, provided that Z does not form a N—N, N—O, N—S, NCH₂N, NCH₂O,     or NCH₂S bond with either group to which it is attached; -   Z² is selected from H, C₁₋₄ alkyl, phenyl, benzyl, C(O)R³, and     S(O)_(p)R^(3c); -   alternatively, when     -   (a) B is other than an optionally substituted carbocycle; and,     -   (b) G₁ is (CH₂)_(u)NR³(CH₂)_(w) and u+w is 1 or 2,         (CH₂)_(u)C(O)NR³(CH₂)_(w), (CH₂)_(u)NR³C(O)(CH₂)_(w),         (CH₂)_(u)S(O)NR³(CH₂)_(w), (CH₂)_(u)S(O)₂NR³(CH₂)_(w), or     -   (CH₂)_(u)NR³S(°)₂(CH₂)_(w);         -   then Z is other than CH₂NH, NHCH₂, C(O)NH, NHC(O), CH₂S(O)₂,             S(O)₂(CH₂), SO₂NH, and NHSO₂; -   alternatively, when     -   (a) B is other than an optionally substituted carbocycle; and,     -   (b) Z is CH₂NH, NHCH₂, C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂),         SO₂NH, and NHSO₂;         -   then G₁ is other than (CR³R^(3a))_(u)NR³(CH₂)_(w) and u+w is             1, 2, 3, or 4, (CH₂)_(u)C(O)NR³(CH₂)_(w),             (CR³R^(3a))_(u)NR³C(O)(CH₂)_(w), (CH₂)_(u)S(O)NR³(CH₂)_(w),             (CR³R^(3a))_(u)S(O)₂NR³(CH₂)_(w), or             (CH₂)_(u)NR³S(O)₂(CH₂)_(w).             [3] In another preferred embodiment, the present invention             provides a novel compound, wherein: -   ring M is substituted with 0–2 R^(1a) and is selected from the     group: -   ring P, including P₁, P₂, P₃, and P₄ is selected from group: -   ring P is substituted with 0–2 R^(1a); -   one of P₄ and M₃ is -Z-A-B and the other -G₁-G; -   G is selected from the group: -   G₁ is absent or is selected from CH₂, CH₂CH₂, CH₂O, OCH₂, NH, CH₂NH,     NHCH₂, CH₂C(O), C(O)CH₂, C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂),     SO₂NH, and NHSO₂, provided that G₁ does not form a N—N, N—O, N—S,     NCH₂N, NCH₂O, or NCH₂S bond with either group to which it is     attached; -   Z is absent or is selected from CH₂O, OCH₂, NH, CH₂NH, NHCH₂,     CH₂C(O), C(O)CH₂, C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and     NHSO₂, provided that Z does not form a N—N, N—O, N—S, NCH₂N, NCH₂O,     or NCH₂S bond with either group to which it is attached; -   alternatively, when     -   (a) B is other than an optionally substituted carbocycle; and,     -   (b) G₁ is CH₂NH, NHCH₂, C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂ (CH₂),         SO₂NH, and NHSO₂;         -   then Z is other than CH₂NH, NHCH₂, C(O)NH, NHC(O), CH₂S(O)₂,             S(O)₂(CH₂), SO₂NH, and NHSO₂; -   alternatively, when     -   (a) B is other than an optionally substituted carbocycle; and,     -   (b) Z is CH₂NH, NHCH₂, C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂),         SO₂NH, and NHSO₂;         -   then G₁ is other than CH₂NH, NHCH₂, C(O)NH, NHC(O),             CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂.             [4] In another preferred embodiment, the present invention             provides a novel compound, wherein: -   ring M is substituted with 0–1 R^(1a) and is selected from the     group: -   ring P, including P₁, P₂, P₃, and P₄ is selected from group -   ring P is substituted with 0–2 R^(1a); -   one of P₄ and M₃ is -Z-A-B and the other -G₁-G; -   G is selected from: -   G₁ is absent.     [5] In another preferred embodiment, the present invention provides     a novel compound, wherein; -   ring M is substituted with 0–1 R^(1a) and is selected from the     group: -   ring P, including P₁, P₂, P₃, and P₄ is selected from group: -   ring P is substituted with 0–2 R^(1a); -   one of P₄ and M₃ is -Z-A-B and the other -G₁-G; -   A is selected from phenyl, pyridyl, and pyrimidyl, and is     substituted with 0–2 R⁴; and, -   B is selected from phenyl, pyrrolidino, N-pyrrolidino-carbonyl,     morpholino, N-morpholino-carbonyl, 1,2,3-triazolyl, imidazolyl, and     benzimidazolyl, and is substituted with 0–1 R^(4a); -   R², at each occurrence, is selected from H, CH₃, CH₂CH₃,     cyclopropylmethyl, cyclobutyl, and cyclopentyl; -   R^(2a), at each occurrence, is H or CH₃; -   alternatively, R² and R^(2a), together with the atom to which they     are attached, combine to form pyrrolidine substituted with 0–2     R^(4b) or piperidine substituted with 0–2 R^(4b); -   R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo,     C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃; -   R^(4a) is selected from C₁₋₄ alkyl, CF₃, (CH₂)_(r)OR²,     (CH₂)_(r)NR²R^(2a), S(O)_(p)R⁵, SO₂NR²R^(2a), and     1-CF₃-tetrazol-2-yl; -   R^(4b), at each occurrence, is selected from H, CH₃, and OH; -   R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl,     and benzyl; and, -   r, at each occurrence, is selected from 0, 1, and 2.     [6] In another preferred embodiment, the present invention provides     a novel compound, wherein; -   A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl,     2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl,     2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, -   B is selected from the group: 2-(aminosulfonyl)phenyl,     2-(methylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl,     2-(methylsulfonyl) phenyl, 2-(N,N-dimethylaminomethyl) phenyl,     2-(N-methylaminomethyl) phenyl,     2-(N-ethyl-N-methylaminomethyl)phenyl,     2-(N-pyrrolidinylmethyl)phenyl, 1-methyl-2-imidazolyl,     2-methyl-1-imidazolyl, 2-(dimethylaminomethyl)-1-imidazolyl,     2-(methylaminomethyl)-1-imidazolyl,     2-(N-(cyclopropylmethyl)aminomethyl)phenyl,     2-(N-(cyclobutyl)aminomethyl)phenyl,     2-(N-(cyclopentyl)aminomethyl)phenyl,     2-(N-(4-hydroxypiperidinyl)methyl)phenyl, and     2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl.

In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders.

In another embodiment, the thromboembolic disorder is selected unstable angina, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.

In another embodiment, the present invention provides a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder

In another embodiment, the present invention provides a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.

In another embodiment, the present invention provides a compound of the present invention for use in therapy.

In another embodiment, the present invention provides the use of a compound of the present invention as described above for the manufacture of a medicament for the treatment of a thromboembolic disorder.

The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

Definitions

The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. Tautomers of compounds shown or described herein are considered to be part of the present invention.

Preferably, the molecular weight of compounds of the present invention is less than about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 grams per mole. More preferably, the molecular weight is less than about 950 grams per mole. Even more preferably, the molecular weight is less than about 850 grams per mole. Still more preferably, the molecular weight is less than about 750 grams per mole.

The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.

The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R⁶) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0–2 R⁶, then said group may optionally be substituted with up to two R⁶ groups and R⁶ at each occurrence is selected independently from the definition of R⁶. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C₁₋₁₀alkyl, is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.

“Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C₁₋₁₀ alkoxy, is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C₃₋₇ cycloalkyl is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkyl groups. Alkenyl” is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that may occur in any stable point along the chain, such as ethenyl and propenyl. C₂₋₁₀ alkenyl is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀alkenyl groups. “Alkynyl” is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl. C₂₋₁₀ Alkynyl is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkynyl groups.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic system” or “heteroary”, is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. “Prodrugs” are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

“Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.

As used herein, “treating” or “treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.

“Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit factor Xa. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27–55, occurs when the effect (in this case, inhibition of factor Xa) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.

Synthesis

The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.

The compounds of the present invention represented by Formula I consist of a group “D-E-G-(CH₂)_(s)-” and a group “-A-B” attached to a [5,6]- or [5,7]-heterobicyclic core structure of varying composition. The five-membered ring can be pyrazole, triazole, isoxazole or isothiazole and this ring can be fused to a variety of six- or seven membered rings including but not limited to piperidinone, pyridinone, pyrimidinone, pyrimidinedione, pyranone, diazepinone, diazepinedione. The following discussion and schemes will describe methods for the syntheses of the heterobicyclic cores and attachment to the groups “G-(CH₂)_(s)-” and “-A-B”.

Benzo fused pyridone compounds of the present invention can be prepared from readily available starting materials as shown in Scheme-1.

Scheme-1, as well as schemes that follow, illustrate that the lactam intermediates can be reduced to their corresponding cyclic amines. As shown above, the lactam can be reduced to its corresponding piperidine via standard reducing techniques such as boron reduction. One of ordinary skill in the art would recognize that this reduction could be performed prior to final assembly or after final assembly of the molecule.

The cyano intermediate obtained in Scheme-1 can be subjected to the Pinner-amidine reaction protocol to afford the corresponding benzamidine (Scheme-2). Alternatively the benzamidine can be obtained by treatment of the cyano precursor with hydroxylamine followed by reduction. The amidines can be acylated with a wide variety of acid chlorides. The intermediate Pinner imidate can also be reacted with alkylamines to afford alklated amidines.

If a substituted cyano phenyl boronic acid is employed in the Suzuki coupling as shown in Scheme-1, then other compounds of this invention can be readily obtained (Scheme-3).

Similarly, if the boronic acid employed in the first step in Scheme-1 is an isoquinoline boronic acid than the isoquinoline precursor is obtained and can be elaborated to the desired aminoisoquinoline product of the present invention.

Other benzo-bicyclics can also be obtained from other commercially available starting materials as shown in

Other compounds of this invention can also be prepared by appropriately choosing substituents to afford compounds of this invention.

Similarly, other compounds such as amino-benzisoxazole, amino-isoquinoline, aminoindazole analogs can also be obtained.

The corresponding benzo-azapyridone analogs can also be prepared via the above methodology.

The amide/amine and sulfide and sulfonamide analogs shown in Scheme-8 can also be prepared from the starting material shown in Scheme-1.

Alternatively the tetralone shown in scheme-8 can be alkylated, acylated and/or sulfonylated, and then subjected to the protocol shown in Scheme-8 to afford other analogs of the present invention (Scheme-9).

The synthesis of tetralones can be accomplished via the Beckmann rearrangement procedure of Tomita et. al. (J. Chem. Soc. 1969, 183), via the carbonylation amidation protocol of Moni et. al. (J. Org. Chein. 1978, 42, 1648) or via the palladium catalyzed protocol of Mahanty et. al. (J. Chem. Soc. Perkin Trans. 1 1997, 17, 2577). These tetralones can be further manipulated by methods well known in the art to afford various compounds of the present invention.

Succinimide analogs can also be obtained via the procedures of Cheng et. al. (J. Het. Chem. 1995, 32(1), 73)(Scheme-10).

The pyridyl bicyclic core can be obtained via the methodology of Seitz et. al. (Chem-Ztg 1990, 114(12), 381) shown in Scheme-11. The tetralone obtained can then be alkylated, or treated with appropriate isocyanates and or treated with appropriate sulfonylchlorides to afford requisite urea and sulfonamide analogs. These can then be subjected to Suzuki reactions and further oxidized to provide compounds of this invention.

In another method of Tada et. al. (J. Het. Chem. 1989, 26, 45), the 3-amido-pyridyl can be alkylated and then cyclyzed to afford the pyrdyl-pyridone analog. Following the methodologies described from schemes 8–11 compounds of these inventions can be obtained.

The pyridazine analogs can be obtained via the methodology of Heinisch et. al. (J. Het. Chem. 1996, 33(6), 1731)(Scheme-13). Following methodologies outlined previously, compounds of this invention can be obtained.

Other compounds of this invention can be prepared following the methodology outlined in scheme-14.

Other compounds of this invention can also be prepared via the intermediates described previously (scheme-15).

The intermediates obtained in schemes 14–15 can than be manipulated to the compounds of this invention via the protocols outlined previously.

Other compounds of this invention can also be prepared via the methodology shown in scheme-16.

The intermediates obtained in scheme-16 can than be manipulated to afford compounds of this invention.

The A-B moieties can be prepared by methods known to those of skill in the art. The following publications, the contents of which are incorporated herein by reference, describe and exemplify means of preparing A-B moieties: WO97/23212, WO97/30971, WO97/38984, WO98/06694, WO98/01428, WO98/28269, WO98/28282, WO99/12903, WO98/57934, WO98/57937, WO98/57951, WO99/32454, WO99/50255, WO00/39131, WO00/38683, WO00/39102, WO01/05784, and WO00/39108.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.

The following tables contain representative examples of the present invention. Each entry in each table is intended to be paired with each formulae at the start of the table. For example, in Tables 1 and 2, example 1 is intended to be paired with each of the formulae.

The following nomenclature is intended for group A in the following tables.

TABLE 1

-   P₄ is G₁-G, wherein G₁ is absent; -   M₃ is Z-A-B, wherein Z is absent; -   G is 4-(methoxy)phenyl;

Ex# A B 1. phenyl 2-(NH₂SO₂)phenyl 2. phenyl 2-(CH₃SO₂)phenyl 3. phenyl 3-NH₂SO₂-4-pyridyl 4. phenyl 3-CH₃SO₂-4-pyridyl 5. phenyl 2-(CH₃NH)phenyl 6. phenyl 3-((CH₃)₂NCH₂)-4-pyridyl 7. phenyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl 8. phenyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl 9. phenyl 2-((CH₃)₂NCH₂)phenyl 10. phenyl 2-((CH₃)NHCH₂)phenyl 11. phenyl 2-((CH₃CH₂)NHCH₂)phenyl 12. phenyl 2-((CH₃CH₂)₂NCH₂)phenyl 13. phenyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl 14. phenyl 2-(((CH₃)₂CH)NHCH₂)phenyl 15. phenyl 2-(((CH₃)₂CH)₂NCH₂)phenyl 16. phenyl 2-((cyclopropyl)NHCH₂)phenyl 17. phenyl 2-((cyclopropyl)₂NCH₂)phenyl 18. phenyl 2-((cyclobutyl)NHCH₂)phenyl 19. phenyl 2-((cyclobutyl)₂NCH₂)phenyl 20. phenyl 2-((cyclopentyl)NHCH₂)phenyl 21. phenyl 2-((cyclopentyl)₂NCH₂)phenyl 22. phenyl 2-((cyclohexyl)NHCH₂)phenyl 23. phenyl 2-((cyclohexyl)₂NCH₂)phenyl 24. phenyl 1-CH₃-2-imidazolyl 25. phenyl 2-CH₃-1-imidazolyl 26. phenyl 2-((CH₃)₂NCH₂)-1-imidazolyl 27. phenyl 2-((CH₃)NHCH₂)-1-imidazolyl 28. phenyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl 29. phenyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl 30. phenyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl 31. phenyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl 32. phenyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl 33. phenyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl 34. phenyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl 35. phenyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl 36. phenyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl 37. phenyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl 38. phenyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl 39. phenyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl 40. phenyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl 41. 2-pyridyl 2-(NH₂SO₂)phenyl 42. 2-pyridyl 2-(CH₃SO₂)phenyl 43. 2-pyridyl 3-NH₂SO₂-4-pyridyl 44. 2-pyridyl 3-CH₃SO₂-4-pyridyl 45. 2-pyridyl 2-(CH₃NH)phenyl 46. 2-pyridyl 3-((CH₃)₂NCH₂)-4-pyridyl 47. 2-pyridyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl 48. 2-pyridyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl 49. 2-pyridyl 2-((CH₃)₂NCH₂)phenyl 50. 2-pyridyl 2-((CH₃)NHCH₂)phenyl 51. 2-pyridyl 2-((CH₃CH₂)NHCH₂)phenyl 52. 2-pyridyl 2-((CH₃CH₂)₂NCH₂)phenyl 53. 2-pyridyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl 54. 2-pyridyl 2-(((CH₃)₂CH)NHCH₂)phenyl 55. 2-pyridyl 2-(((CH₃)₂CH)₂NCH₂)phenyl 56. 2-pyridyl 2-((cyclopropyl)NHCH₂)phenyl 57. 2-pyridyl 2-((cyclopropyl)₂NCH₂)phenyl 58. 2-pyridyl 2-((cyclobutyl)NHCH₂)phenyl 59. 2-pyridyl 2-((cyclobutyl)₂NCH₂)phenyl 60. 2-pyridyl 2-((cyclopentyl)NHCH₂)phenyl 61. 2-pyridyl 2-((cyclopentyl)₂NCH₂)phenyl 62. 2-pyridyl 2-((cyclohexyl)NHCH₂)phenyl 63. 2-pyridyl 2-((cyclohexyl)₂NCH₂)phenyl 64. 2-pyridyl 1-CH₃-2-imidazolyl 65. 2-pyridyl 2-CH₃-1-imidazolyl 66. 2-pyridyl 2-((CH₃)₂NCH₂)-1-imidazolyl 67. 2-pyridyl 2-((CH₃)NHCH₂)-1-imidazolyl 68. 2-pyridyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl 69. 2-pyridyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl 70. 2-pyridyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl 71. 2-pyridyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl 72. 2-pyridyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl 73. 2-pyridyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl 74. 2-pyridyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl 75. 2-pyridyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl 76. 2-pyridyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl 77. 2-pyridyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl 78. 2-pyridyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl 79. 2-pyridyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl 80. 2-pyridyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl 81. 3-pyridyl 2-(NH₂SO₂)phenyl 82. 3-pyridyl 2-(CH₃SO₂)phenyl 83. 3-pyridyl 3-NH₂SO₂-4-pyridyl 84. 3-pyridyl 3-CH₃SO₂-4-pyridyl 85. 3-pyridyl 2-(CH₃NH)phenyl 86. 3-pyridyl 3-((CH₃)₂NCH₂)-4-pyridyl 87. 3-pyridyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl 88. 3-pyridyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl 89. 3-pyridyl 2-((CH₃)₂NCH₂)phenyl 90. 3-pyridyl 2-((CH₃)NHCH₂)phenyl 91. 3-pyridyl 2-((CH₃CH₂)NHCH₂)phenyl 92. 3-pyridyl 2-((CH₃CH₂)₂NCH₂)phenyl 93. 3-pyridyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl 94. 3-pyridyl 2-(((CH₃)₂CH)NHCH₂)phenyl 95. 3-pyridyl 2-(((CH₃)₂CH)₂NCH₂)phenyl 96. 3-pyridyl 2-((cyclopropyl)NHCH₂)phenyl 97. 3-pyridyl 2-((cyclopropyl)₂NCH₂)phenyl 98. 3-pyridyl 2-((cyclobutyl)NHCH₂)phenyl 99. 3-pyridyl 2-((cyclobutyl)₂NCH₂)phenyl 100. 3-pyridyl 2-((cyclopentyl)NHCH₂)phenyl 101. 3-pyridyl 2-((cyclopentyl)₂NCH₂)phenyl 102. 3-pyridyl 2-((cyclohexyl)NHCH₂)phenyl 103. 3-pyridyl 2-((cyclohexyl)₂NCH₂)phenyl 104. 3-pyridyl 1-CH₃-2-imidazolyl 105. 3-pyridyl 2-CH₃-1-imidazolyl 106. 3-pyridyl 2-((CH₃)₂NCH₂)-1-imidazolyl 107. 3-pyridyl 2-((CH₃)NHCH₂)-1-imidazolyl 108. 3-pyridyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl 109. 3-pyridyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl 110. 3-pyridyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl 111. 3-pyridyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl 112. 3-pyridyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl 113. 3-pyridyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl 114. 3-pyridyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl 115. 3-pyridyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl 116. 3-pyridyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl 117. 3-pyridyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl 118. 3-pyridyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl 119. 3-pyridyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl 120. 3-pyridyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl 121. 2-pyrimidyl 2-(NH₂SO₂)phenyl 122. 2-pyrimidyl 2-(CH₃SO₂)phenyl 123. 2-pyrimidyl 3-NH₂SO₂-4-pyridyl 124. 2-pyrimidyl 3-CH₃SO₂-4-pyridyl 125. 2-pyrimidyl 2-(CH₃NH)phenyl 126. 2-pyrimidyl 3-((CH₃)₂NCH₂)-4-pyridyl 127. 2-pyrimidyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl 128. 2-pyrimidyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl 129. 2-pyrimidyl 2-((CH₃)₂NCH₂)phenyl 130. 2-pyrimidyl 2-((CH₃)NHCH₂)phenyl 131. 2-pyrimidyl 2-((CH₃CH₂)NHCH₂)phenyl 132. 2-pyrimidyl 2-((CH₃CH₂)₂NCH₂)phenyl 133. 2-pyrimidyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl 134. 2-pyrimidyl 2-(((CH₃)₂CH)NHCH₂)phenyl 135. 2-pyrimidyl 2-(((CH₃)₂CH)₂NCH₂)phenyl 136. 2-pyrimidyl 2-((cyclopropyl)NHCH₂)phenyl 137. 2-pyrimidyl 2-((cyclopropyl)₂NCH₂)phenyl 138. 2-pyrimidyl 2-((cyclobutyl)NHCH₂)phenyl 139. 2-pyrimidyl 2-((cyclobutyl)₂NCH₂)phenyl 140. 2-pyrimidyl 2-((cyclopentyl)NHCH₂)phenyl 141. 2-pyrimidyl 2-((cyclopentyl)₂NCH₂)phenyl 142. 2-pyrimidyl 2-((cyclohexyl)NHCH₂)phenyl 143. 2-pyrimidyl 2-((cyclohexyl)₂NCH₂)phenyl 144. 2-pyrimidyl 1-CH₃-2-imidazolyl 145. 2-pyrimidyl 2-CH₃-1-imidazolyl 146. 2-pyrimidyl 2-((CH₃)₂NCH₂)-1-imidazolyl 147. 2-pyrimidyl 2-((CH₃)NHCH₂)-1-imidazolyl 148. 2-pyrimidyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl 149. 2-pyrimidyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl 150. 2-pyrimidyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl 151. 2-pyrimidyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl 152. 2-pyrimidyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl 153. 2-pyrimidyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl 154. 2-pyrimidyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl 155. 2-pyrimidyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl 156. 2-pyrimidyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl 157. 2-pyrimidyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl 158. 2-pyrimidyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl 159. 2-pyrimidyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl 160. 2-pyrimidyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl 161. 5-pyrimidyl 2-(NH₂SO₂)phenyl 162. 5-pyrimidyl 2-(CH₃SO₂)phenyl 163. 5-pyrimidyl 3-NH₂SO₂-4-pyridyl 164. 5-pyrimidyl 3-CH₃SO₂-4-pyridyl 165. 5-pyrimidyl 2-(CH₃NH)phenyl 166. 5-pyrimidyl 3-((CH₃)₂NCH₂)-4-pyridyl 167. 5-pyrimidyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl 168. 5-pyrimidyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl 169. 5-pyrimidyl 2-((CH₃)₂NCH₂)phenyl 170. 5-pyrimidyl 2-((CH₃)NHCH₂)phenyl 171. 5-pyrimidyl 2-((CH₃CH₂)NHCH₂)phenyl 172. 5-pyrimidyl 2-((CH₃CH₂)₂NCH₂)phenyl 173. 5-pyrimidyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl 174. 5-pyrimidyl 2-(((CH₃)₂CH)NHCH₂)phenyl 175. 5-pyrimidyl 2-(((CH₃)₂CH)₂NCH₂)phenyl 176. 5-pyrimidyl 2-((cyclopropyl)NHCH₂)phenyl 177. 5-pyrimidyl 2-((cyclopropyl)₂NCH₂)phenyl 178. 5-pyrimidyl 2-((cyclobutyl)NHCH₂)phenyl 179. 5-pyrimidyl 2-((cyclobutyl)₂NCH₂)phenyl 180. 5-pyrimidyl 2-((cyclopentyl)NHCH₂)phenyl 181. 5-pyrimidyl 2-((cyclopentyl)₂NCH₂)phenyl 182. 5-pyrimidyl 2-((cyclohexyl)NHCH₂)phenyl 183. 5-pyrimidyl 2-((cyclohexyl)₂NCH₂)phenyl 184. 5-pyrimidyl 1-CH₃-2-imidazolyl 185. 5-pyrimidyl 2-CH₃-1-imidazolyl 186. 5-pyrimidyl 2-((CH₃)₂NCH₂)-1-imidazolyl 187. 5-pyrimidyl 2-((CH₃)NHCH₂)-1-imidazolyl 188. 5-pyrimidyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl 189. 5-pyrimidyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl 190. 5-pyrimidyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl 191. 5-pyrimidyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl 192. 5-pyrimidyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl 193. 5-pyrimidyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl 194. 5-pyrimidyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl 195. 5-pyrimidyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl 196. 5-pyrimidyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl 197. 5-pyrimidyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl 198. 5-pyrimidyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl 199. 5-pyrimidyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl 200. 5-pyrimidyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl 201. 2-Cl-phenyl 2-(NH₂SO₂)phenyl 202. 2-Cl-phenyl 2-(CH₃SO₂)phenyl 203. 2-Cl-phenyl 3-NH₂SO₂-4-pyridyl 204. 2-Cl-phenyl 3-CH₃SO₂-4-pyridyl 205. 2-Cl-phenyl 2-(CH₃NH)phenyl 206. 2-Cl-phenyl 3-((CH₃)₂NCH₂)-4-pyridyl 207. 2-Cl-phenyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl 208. 2-Cl-phenyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl 209. 2-Cl-phenyl 2-((CH₃)₂NCH₂)phenyl 210. 2-Cl-phenyl 2-((CH₃)NHCH₂)phenyl 211. 2-Cl-phenyl 2-((CH₃CH₂)NHCH₂)phenyl 212. 2-Cl-phenyl 2-((CH₃CH₂)₂NCH₂)phenyl 213. 2-Cl-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl 214. 2-Cl-phenyl 2-(((CH₃)₂CH)NHCH₂)phenyl 215. 2-Cl-phenyl 2-(((CH₃)₂CH)₂NCH₂)phenyl 216. 2-Cl-phenyl 2-((cyclopropyl)NHCH₂)phenyl 217. 2-Cl-phenyl 2-((cyclopropyl)₂NCH₂)phenyl 218. 2-Cl-phenyl 2-((cyclobutyl)NHCH₂)phenyl 219. 2-Cl-phenyl 2-((cyclobutyl)₂NCH₂)phenyl 220. 2-Cl-phenyl 2-((cyclopentyl)NHCH₂)phenyl 221. 2-Cl-phenyl 2-((cyclopentyl)₂NCH₂)phenyl 222. 2-Cl-phenyl 2-((cyclohexyl)NHCH₂)phenyl 223. 2-Cl-phenyl 2-((cyclohexyl)₂NCH₂)phenyl 224. 2-Cl-phenyl 1-CH₃-2-imidazolyl 225. 2-Cl-phenyl 2-CH₃-1-imidazolyl 226. 2-Cl-phenyl 2-((CH₃)₂NCH₂)-1-imidazolyl 227. 2-Cl-phenyl 2-((CH₃)NHCH₂)-1-imidazolyl 228. 2-Cl-phenyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl 229. 2-Cl-phenyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl 230. 2-Cl-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl 231. 2-Cl-phenyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl 232. 2-Cl-phenyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl 233. 2-Cl-phenyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl 234. 2-Cl-phenyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl 235. 2-Cl-phenyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl 236. 2-Cl-phenyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl 237. 2-Cl-phenyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl 238. 2-Cl-phenyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl 239. 2-Cl-phenyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl 240. 2-Cl-phenyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl 241. 2-F-phenyl 2-(NH₂SO₂)phenyl 242. 2-F-phenyl 2-(CH₃SO₂)phenyl 243. 2-F-phenyl 3-NH₂SO₂-4-pyridyl 244. 2-F-phenyl 3-CH₃SO₂-4-pyridyl 245. 2-F-phenyl 2-(CH₃NH)phenyl 246. 2-F-phenyl 3-((CH₃)₂NCH₂)-4-pyridyl 247. 2-F-phenyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl 248. 2-F-phenyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl 249. 2-F-phenyl 2-((CH₃)₂NCH₂)phenyl 250. 2-F-phenyl 2-((CH₃)NHCH₂)phenyl 251. 2-F-phenyl 2-((CH₃CH₂)NHCH₂)phenyl 252. 2-F-phenyl 2-((CH₃CH₂)₂NCH₂)phenyl 253. 2-F-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl 254. 2-F-phenyl 2-(((CH₃)₂CH)NHCH₂)phenyl 255. 2-F-phenyl 2-(((CH₃)₂CH)₂NCH₂)phenyl 256. 2-F-phenyl 2-((cyclopropyl)NHCH₂)phenyl 257. 2-F-phenyl 2-((cyclopropyl)₂NCH₂)phenyl 258. 2-F-phenyl 2-((cyclobutyl)NHCH₂)phenyl 259. 2-F-phenyl 2-((cyclobutyl)₂NCH₂)phenyl 260. 2-F-phenyl 2-((cyclopentyl)NHCH₂)phenyl 261. 2-F-phenyl 2-((cyclopentyl)₂NCH₂)phenyl 262. 2-F-phenyl 2-((cyclohexyl)NHCH₂)phenyl 263. 2-F-phenyl 2-((cyclohexyl)₂NCH₂)phenyl 264. 2-F-phenyl 1-CH₃-2-imidazolyl 265. 2-F-phenyl 2-CH₃-1-imidazolyl 266. 2-F-phenyl 2-((CH₃)₂NCH₂)-1-imidazolyl 267. 2-F-phenyl 2-((CH₃)NHCH₂)-1-imidazolyl 268. 2-F-phenyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl 269. 2-F-phenyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl 270. 2-F-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl 271. 2-F-phenyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl 272. 2-F-phenyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl 273. 2-F-phenyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl 274. 2-F-phenyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl 275. 2-F-phenyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl 276. 2-F-phenyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl 277. 2-F-phenyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl 278. 2-F-phenyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl 279. 2-F-phenyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl 280. 2-F-phenyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl 281. 2,6-diF-phenyl 2-(NH₂SO₂)phenyl 282. 2,6-diF-phenyl 2-(CH₃SO₂)phenyl 283. 2,6-diF-phenyl 3-NH₂SO₂-4-pyridyl 284. 2,6-diF-phenyl 3-CH₃SO₂-4-pyridyl 285. 2,6-diF-phenyl 2-(CH₃NH)phenyl 286. 2,6-diF-phenyl 3-((CH₃)₂NCH₂)-4-pyridyl 287. 2,6-diF-phenyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl 288. 2,6-diF-phenyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl 289. 2,6-diF-phenyl 2-((CH₃)₂NCH₂)phenyl 290. 2,6-diF-phenyl 2-((CH₃)NHCH₂)phenyl 291. 2,6-diF-phenyl 2-((CH₃CH₂)NHCH₂)phenyl 292. 2,6-diF-phenyl 2-((CH₃CH₂)₂NCH₂)phenyl 293. 2,6-diF-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl 294. 2,6-diF-phenyl 2-(((CH₃)₂CH)NHCH₂)phenyl 295. 2,6-diF-phenyl 2-(((CH₃)₂CH)₂NCH₂)phenyl 296. 2,6-diF-phenyl 2-((cyclopropyl)NHCH₂)phenyl 297. 2,6-diF-phenyl 2-((cyclopropyl)₂NCH₂)phenyl 298. 2,6-diF-phenyl 2-((cyclobutyl)NHCH₂)phenyl 299. 2,6-diF-phenyl 2-((cyclobutyl)₂NCH₂)phenyl 300. 2,6-diF-phenyl 2-((cyclopentyl)NHCH₂)phenyl 301. 2,6-diF-phenyl 2-((cyclopentyl)₂NCH₂)phenyl 302. 2,6-diF-phenyl 2-((cyclohexyl)NHCH₂)phenyl 303. 2,6-diF-phenyl 2-((cyclohexyl)₂NCH₂)phenyl 304. 2,6-diF-phenyl 1-CH₃-2-imidazolyl 305. 2,6-diF-phenyl 2-CH₃-1-imidazolyl 306. 2,6-diF-phenyl 2-((CH₃)₂NCH₂)-1-imidazolyl 307. 2,6-diF-phenyl 2-((CH₃)NHCH₂)-1-imidazolyl 308. 2,6-diF-phenyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl 309. 2,6-diF-phenyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl 310. 2,6-diF-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl 311. 2,6-diF-phenyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl 312. 2,6-diF-phenyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl 313. 2,6-diF-phenyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl 314. 2,6-diF-phenyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl 315. 2,6-diF-phenyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl 316. 2,6-diF-phenyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl 317. 2,6-diF-phenyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl 318. 2,6-diF-phenyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl 319. 2,6-diF-phenyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl 320. 2,6-diF-phenyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl 321. piperidinyl 2-(NH₂SO₂)phenyl 322. piperidinyl 2-(CH₃SO₂)phenyl 323. piperidinyl 3-NH₂SO₂-4-pyridyl 324. piperidinyl 3-CH₃SO₂-4-pyridyl 325. piperidinyl 2-(CH₃NH)phenyl 326. piperidinyl 3-((CH₃)₂NCH₂)-4-pyridyl 327. piperidinyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl 328. piperidinyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl 329. piperidinyl 2-((CH₃)₂NCH₂)phenyl 330. piperidinyl 2-((CH₃)NHCH₂)phenyl 331. piperidinyl 2-((CH₃CH₂)NHCH₂)phenyl 332. piperidinyl 2-((CH₃CH₂)₂NCH₂)phenyl 333. piperidinyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl 334. piperidinyl 2-(((CH₃)₂CH)NHCH₂)phenyl 335. piperidinyl 2-(((CH₃)₂CH)₂NCH₂)phenyl 336. piperidinyl 2-((cyclopropyl)NHCH₂)phenyl 337. piperidinyl 2-((cyclopropyl)₂NCH₂)phenyl 338. piperidinyl 2-((cyclobutyl)NHCH₂)phenyl 339. piperidinyl 2-((cyclobutyl)₂NCH₂)phenyl 340. piperidinyl 2-((cyclopentyl)NHCH₂)phenyl 341. piperidinyl 2-((cyclopentyl)₂NCH₂)phenyl 342. piperidinyl 2-((cyclohexyl)NHCH₂)phenyl 343. piperidinyl 2-((cyclohexyl)₂NCH₂)phenyl 344. piperidinyl 1-CH₃-2-imidazolyl 345. piperidinyl 2-CH₃-1-imidazolyl 346. piperidinyl 2-((CH₃)₂NCH₂)-1-imidazolyl 347. piperidinyl 2-((CH₃)NHCH₂)-1-imidazolyl 348. piperidinyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl 349. piperidinyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl 350. piperidinyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl 351. piperidinyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl 352. piperidinyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl 353. piperidinyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl 354. piperidinyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl 355. piperidinyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl 356. piperidinyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl 357. piperidinyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl 358. piperidinyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl 359. piperidinyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl 360. piperidinyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl 361. piperidinyl isopropyl

Examples 362–6498 use the corresponding A and B groups from Examples 1–361 and the recited G group.

Examples 362–722, G is 3-aminoindazol-6-yl;

Examples 723–1083, G is 3-amidophenyl;

Examples 1084–1444, G is 2-(aminomethyl)phenyl;

Examples 1445–1805, G is 3-(aminomethyl)phenyl;

Examples 1806–2166, G is 2-(aminomethyl)-3-fluorophenyl;

Examples 2167–2527, G is 2-(aminomethyl)-4-fluorophenyl;

Examples 2528–2888, G is 4-Cl-2-pyridyl;

Examples 2889–3249, G is 4-chlorophenyl;

Examples 3250–3610, G is 3-amino-4-chloro-phenyl;

Examples 3611–3971, G is 3-amidino-phenyl;

Examples 3972–4332, G is 1-aminoisoquinolin-6-yl;

Examples 4333–4693, G is 1-aminoisoquinolin-7-yl;

Examples 4694–5054, G is 4-aminoquinazol-6-yl;

Examples 5055–5415, G is 4-aminoquinazol-7-yl;

Examples 5416–5776, G is 3-aminobenzisoxazol-5-yl;

Examples 5777–6137, G is 3-aminobenzisoxazol-6-yl; and,

Examples 6138–6498, G is 3-aminoindazol-5-yl.

Table 2

Examples 1–6498 of Table 1, wherein G₁ is NH₂C(O).

Table 3

Examples 1–6498 of Table 1, wherein G₁ is C(O)NH₂.

Utility

The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. In general, a thromboembolic disorder is a circulatory disease caused by blood clots (i.e., diseases involving platelet activation and/or platelet aggregation). The term “thromboembolic disorders” as used herein includes arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders. The term “thromboembolic disorders” as used herein includes specific disorders selected from, but not limited to, unstable angina, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis. It is noted that thrombosis includes occlusion (e.g. after a bypass) and reocclusion (e.g., during or after percutaneous translumianl coronary angioplasty). The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.

The effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Diapharma/Chromogenix, West Chester, Ohio) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, K_(i).

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant, K_(m), for substrate hydrolysis was determined at 25° C. using the method of Lineweaver and Burk. Values of K_(i) were determined by allowing 0.2–0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, Ind.) to react with the substrate (0.20 mM–1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25–30 minutes. The following relationship was used to calculate K_(i) values: (v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m))) where:

-   -   v_(o) is the velocity of the control in the absence of         inhibitor;     -   v_(s) is the velocity in the presence of inhibitor;     -   I is the concentration of inhibitor;     -   K_(i) is the dissociation constant of the enzyme:inhibitor         complex;     -   S is the concentration of substrate;     -   K_(m) is the Michaelis constant.

Compounds tested in the above assay are considered to be active if they exhibit a K_(i) of ≦10 μM. Preferred compounds of the present invention have K_(i)'s of ≦1 μM. More preferred compounds of the present invention have K_(i)'s of ≦0.1 μM. Even more preferred compounds of the present invention have K_(i)'s of ≦0.01 μM. Still more preferred compounds of the present invention have K_(i)'s of ≦0.001 μM. Using the methodology described above, a number of compounds of the present invention were found to exhibit K_(i)'s of ≦10 μM, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.

The antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. In this model, rabbits weighing 2–3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. A F saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of a piece of 6-cm tygon tubing that contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein. The exposure of flowing blood to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v./ i.p., s.c., or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID₅₀ values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.

The compounds of the present invention may also be useful as inhibitors of serine proteases, notably human thrombin, Factor VIIa, Factor IXa, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.

Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. In vitro inhibition constants were determined by the method is described by Kettner et al. in J. Biol. Chem. 265, 18289–18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, Tex.) was monitored spectrophotometrically. Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm that arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a K_(i) of less than 10 μm, thereby confirming the utility of the compounds of the present invention as effective thrombin inhibitors.

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeutically effective amount. By “therapeutically effective amount” it is meant an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.

By “administered in combination” or “combination therapy” it is meant that a compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin and heparin (either unfractionated heparin or any commercially available low molecular weight heparin), synthetic pentasaccharide, direct acting thrombin inhibitors including hirudin and argatrobanas well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam are preferred. Other suitable anti-platelet agents include ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine and clopidogrel are also preferred compounds since they are known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include IIb/IIIa antagonists, including tirofiban, eptifibatide, and abciximab, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.

The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin, argatroban, and melagatran, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal α-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.

The term thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator and modified forms thereof, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in EP 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

Administration of the compounds of the present invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.

The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving factor Xa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnostic assays involving factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but not in the presence of a compound of the present invention, then one would conclude factor Xa was present.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5–95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P, and 0.025 mL of vanillin.

Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

Where the compounds of the present invention are administered in combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.

Where the compounds of Formula I are administered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of w Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70–80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. 

1. A compound of Formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

ring M, including M₁ and M₂, is ring M is substituted with 0–2 R^(1a);

ring P, including P₁, P₂, P₃, and P₄ is: ring P is substituted with 0–2 R^(1a); P₄-G₁-G; M₃is -Z-A-B; G is a group of formula IIa:

ring D, including the two atoms of Ring E to which it is attached, is a 5–6 membered non-aromatic ring consisting of carbon atoms, 0–1 double bonds, and 0–2 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and D is substituted with 0–2 R; alternatively, ring D, including the two atoms of Ring E to which it is attached, is a 5–6 membered aromatic system consisting of carbon atoms and 0–2 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and D is substituted with 0–2 R; E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1–2 R; alternatively, the bridging portion of ring D is absent, and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and ring E is substituted with 1–2 R; alternatively, the bridging portion of ring D is absent, ring E is selected from phenyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and ring E is substituted with 1 R and with a 5–6 membered heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)_(p) substituted with 0–1 carbonyls, 1–2 R and having 0–3 ring double bonds; R is selected from H, C₁₋₄ alkyl, F, Cl, Br, I, OH, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, CN, C(═NR⁸)NR⁷R⁹, NHC(═NR⁸)NR⁷R⁹, NR⁸CH(═NR⁷), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, C(═NH)NH₂, CH₂NH₂, CH₂NH(C₁₋₃ alkyl), CH₂N(C₁₋₃ alkyl)₂, CH₂CH₂NH₂, CH₂CH₂NH(C₁₋₃ alkyl), CH₂CH₂N(C₁₋₃ alkyl)₂, (CR⁸R⁹)_(t)C(O)H, (CR₈R⁹)_(t)C(O)R^(2c), (CR⁸R⁹)_(t)NR⁷R⁸, (CR⁸R⁹)_(t)C(O)NR⁷R⁸, (CR⁸R⁹)_(t)NR⁷C(O)R⁷, (CR⁸R⁹)_(t)OR³, (CR⁸R⁹)_(t)S(O)_(p)NR⁷R⁸, (CR⁸R⁹)_(t)NR⁷S(O)_(p)R⁷, (CR⁸R⁹)_(t)SR³, (CR⁸R⁹)_(t)S(O)R³, (CR⁸R⁹)_(t)S(O)₂R³, and OCF₃, provided that S(O)_(p)R⁷ forms other than S(O)₂H or S(O)H; alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy; A is phenyl substituted with 0–2 R⁴; B is selected from: Y, X—Y, (CH₂)₀₋₂C(O)NR²R^(2a), (CH₂)₀₋₂NR²R^(2a), C(═NR²)NR²R^(2a), and NR²C(═NR²)NR²R^(2a), provided that Z and B are attached to different atoms on A; G₁ is absent; X is selected from —(CR²R^(2a))₁₋₄—, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —C(═NR^(1c))—, —CR² (NR^(1c)R²)—, —CR² (OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S—, —S(O)—, —S(O)₂—SCR²R^(2a)—, —S(O)CR²R^(2a)—, —S(O)₂CR²R^(2a)—, —CR²R^(2a)S—, —CR²R^(2a)S(O)—, —CR²R^(2a)S(O)₂—, —S(O)₂NR²—, —NR²S(O)₂—, —NR²S(O)₂CR²R^(2a)—, —CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—, —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—, —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—; Y is selected from: C₃₋₁₀ carbocycle substituted with 0–2 R^(4a), and, 5–10 membered heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)_(p) substituted with 0–2 R^(4a); Z is absent; R^(1a) is selected from H, —(CH₂)_(r)—R^(1b), —CH═CH—R^(1b), NCH₂R^(1c), OCH₂R^(1c), SCH₂R^(1c), NH(CH₂)₂(CH₂)_(t)R^(1b), O(CH₂)₂(CH₂)_(t)R^(1b), S(CH₂)₂(CH₂)_(t)R^(1b), S(O)_(p)(CH₂)_(r)R^(1d), O(CH₂)_(r)R^(1d), NR³(CH₂)_(r)R^(1d), OC(O)NR³(CH₂)_(r)R^(1d), NR³C(O)NR³(CH₂)_(r)R^(1d), NR³C(O)O(CH₂)_(r)R^(1d), and NR³C(O)(CH₂)_(r)R^(1d), provided that R^(1a) forms other than an N-halo, N—N, N—S, N—O, or N—CN bond; alternatively, when two R^(1a)s are attached to adjacent carbon atoms, together with the atoms to which they are attached they form a 5–7 membered ring consisting of: carbon atoms and 0–2 heteroatoms selected from the group consisting of N, O, and S(O)_(p), this ring being substituted with 0–2 R^(4b) and comprising: 0–3 double bonds; R^(1b) is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO, (CF₂)_(r)CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c), OC(O)R², (CF₂)_(r)CO₂R^(2a), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², C(═NR^(2c))NR²R^(2a), NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a), OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a), C(O)NR² (CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆ carbocycle substituted with 0–2 R^(4a), and 5–10 membered heterocycle consisting of carbon atoms and from 1–4 heteroatoms selected from the group consisting of N, O, and S(O)_(p) substituted with 0–2 R^(4a), provided that R^(1b) forms other than an N-halo, N—N, N—S, N—O, or N—CN bond; R^(1c) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a), S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a); R^(1d) is selected from C₃₋₆ carbocycle substituted with 0–2 R^(4a), and 5–10 membered heterocycle consisting of carbon atoms and from 1–4 heteroatoms selected from the group consisting of N, O, and S(O)_(p) substituted with 0–2 R^(4a), provided that R^(1d) forms other than an N—N, N—S, or N—O bond; R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocycle substituted with 0–2 R^(4b), a C₃₋₆ carbocyclic-CH₂-residue substituted with 0–2 R^(4b), and 5–6 membered heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)_(p) substituted with 0–2 R^(4b); R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocycle substituted with 0–2 R^(4b), and 5–6 membered heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)_(p) substituted with 0–2 R^(4b); R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocycle substituted with 0–2 R^(4b), and 5–6 membered heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)_(p) substituted with 0–2 R^(4b); R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0–2 R^(4b), and 5–6 membered heterocyclic system containing from 1–4 heteroatoms selected from the group consisting of N, O, and S(O)_(p) substituted with 0–2 R^(4b); alternatively, R² and R^(2a), together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0–2 R^(4b) and consisting of: 0–1 additional heteroatoms selected from the group consisting of N, O, and S(O)_(p); R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl; R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, benzyl, and phenyl; R^(3b), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl; R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, benzyl, and phenyl; R^(3d), at each occurrence, is selected from H, C₁₋₄ alkyl, C₁₋₄ alkyl-phenyl, and C(═O)R^(3c); R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a), C(═NR²) NR²R^(2a), C(═NS(O)₂R⁵)NR²R^(2a), NHC(═NR²) NR²R^(2a), C(O)NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, NCH₂R^(1c), OCH₂R^(1c), SCH₂R^(1c), N(CH₂)₂(CH₂)_(t)R^(1b), O(CH₂)₂(CH₂)_(t)R^(1b), and S(CH₂)₂(CH₂)_(t)R^(1b); alternatively, one R⁴ is a 5–6 membered aromatic heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)_(p); R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², (CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, Cl, Br, F, I, C₁₋₄ alkyl, s-CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a), (CH₂)_(r)N═CHOR³, (O)NH(CH₂)₂NR²R^(2a), NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃; alternatively, one R⁴a is phenyl substituted with 0–1 R⁵ or a 5–6 membered aromatic heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)_(p) substituted with 0–1 R⁵; R^(4b), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR³, F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR³C, NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a), C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF₃; R⁵, at each occurrence, is selected from H, C₁₋₆ alkyl, ═O, (CH₂)_(r)OR³, F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a), CH(═NOR^(3d)), C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, (CF₂)_(r)CF₃, phenyl substituted with 0–2 R⁶, naphthyl substituted with 0–2 R⁶, and benzyl substituted with 0–2 R⁶; R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), NR²C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl; R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl, and (CH₂)_(n)-phenyl; alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated, ring which contains from 0–1 additional heteroatoms selected from the group consisting of N, O, and S(O)_(p); R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl, and (CH₂) n-phenyl; n, at each occurrence, is selected from 0, 1, 2, and 3; p, at each occurrence, is selected from 0, 1, and 2; r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6; and, t, at each occurrence, is selected from 0, 1, 2, and
 3. 2. A compound according to claim 1, wherein: G is selected from the group:

B is selected from Y, X—Y, CH₂NR²R^(2a), and CH₂CH₂NR²R^(2a); X is selected from —(CR²R^(2a))₁₋₄, —C(O)—, —C(═NR^(1c))—, —CR²(NR^(1c)R²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—; Y is selected from one of the following carbocyclic and heterocyclic systems that are substituted with 0–2 R^(4a); cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl; alternatively, Y is selected from the following bicyclic heteroaryl ring systems:

K is selected from O, S, NH, and N.
 3. A compound according to claim 2, wherein: G is selected from the group:


4. A compound according to claim 3, wherein: ring M is substituted with 0–1 R^(1a); G is selected from:


5. A compound according to claim 4, wherein: B is selected from phenyl, pyrrolidino, N-pyrrolidino-carbonyl, morpholino, N-morpholino-carbonyl, 1,2,3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 0–1 R^(4a); R², at each occurrence, is selected from H, CH₃, CH₂CH₃, cyclopropylmethyl, cyclobutyl, and cyclopentyl; R^(2a), at each occurrence, is H or CH₃; alternatively, R² and R^(2a), together with the atom to which they are attached, combine to form pyrrolidine substituted with 0–2 R^(4b) or piperidine substituted with 0–2 R^(4b); R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF_(3;) R^(4a) is selected from C₁₋₄ alkyl, CF₃, (CH₂)_(r)OR², (CH₂)_(r)NR²R^(2a), S(O)_(p)R⁵, SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl; R^(4b), at each occurrence, is selected from H, CH₃, and OH; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl; and, r, at each occurrence, is selected from 0, 1, and
 2. 6. A compound according to claim 5, wherein: A is selected from the group: phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, B is selected from the group: 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl) phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 2-(N,N-dimethylaminomethyl)phenyl, 2-(N-methylaminomethyl)phenyl, 2-(N-ethyl-N-methylaminomethyl)phenyl, 2-(N-pyrrolidinylmethyl)phenyl, 1-methyl-2-imidazolyl, 2-methyl-1-imidazolyl, 2-(dimethylaminomethyl)-1-imidazolyl, 2-(methylaminomethyl)-1-imidazolyl, 2-(N-(cyclopropylmethyl)aminomethyl)phenyl, 2-(N-(cyclobutyl)aminomethyl)phenyl, 2-(N-(cyclopentyl)aminomethyl)phenyl, 2-(N-(4-hydroxypiperidinyl)methyl)phenyl, and 2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl.
 7. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof.
 8. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof.
 9. A method according to claim 8, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders.
 10. A method according to claim 9, wherein the thromboembolic disorder is selected unstable angina, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
 11. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt form thereof.
 12. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt form thereof.
 13. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt form thereof.
 14. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof.
 15. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 6 or a pharmaceutically acceptable salt form thereof.
 16. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt form thereof.
 17. A method according to claim 16, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders.
 18. A method according to claim 17, wherein the thromboembolic disorder is selected unstable angina, first myocardial infarction, recurrent myocardial infarction, ischeinic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
 19. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt form thereof.
 20. A method according to claim 19, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders.
 21. A method according to claim 20, wherein the thromboembolic disorder is selected unstable angina, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
 22. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt form thereof.
 23. A method according to claim 22, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders.
 24. A method according to claim 23, wherein the thromboembolic disorder is selected unstable angina, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
 25. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof.
 26. A method according to claim 25, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders.
 27. A method according to claim 26, wherein the thromboembolic disorder is selected unstable angina, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
 28. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 6 or a pharmaceutically acceptable salt form thereof.
 29. A method according to claim 28, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders.
 30. A method according to claim 29, wherein the thromboembolic disorder is selected unstable angina, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis. 